Despite significant improvements in living standards and biomedical technologies over the past century, the global burden of infectious diseases remains exceedingly high and is a major cause of public health, economic and social problems. According to World Health Organization (WHO) statistics, infectious and parasitic diseases such as pneumonia, tuberculosis, meningitis, diarrheal diseases, HIV and malaria are the second leading causes of death worldwide. The widespread and often indiscriminate use of antibiotics in industrialized nations further fuels the problem by contributing to the rapid emergence of drug resistant pathogens, making infectious diseases increasingly difficult to control with the existing classes of antibiotics. The exploding crisis of antibiotic-resistant infections coupled with the on-going dearth in new small-molecule antibiotics development, have spurred considerable efforts toward the discovery and development of membrane active antimicrobial peptides (AMPs) as an alternative class of antimicrobial agents. Naturally occurring antimicrobial peptides, also known as ‘host defence peptides’, were first discovered as components of the innate immunity, forming the first line of defence against invading pathogens in all living organisms. Unlike conventional antibiotics that inhibit specific biosynthetic pathways such as cell wall or protein synthesis, the majority of the cationic antimicrobial peptides exert their activities via physical disruption of the more negatively charged microbial membrane lipid bilayers to induce leakage of cytoplasmic components leading to cell death. The physical nature of membrane disruption is believed to result in a lower likelihood for drug resistance development as it becomes metabolically ‘costlier’ for the microorganism to mutate or to repair its membrane components at the same rate as the damage is being inflicted.
Although more than 1700 naturally occurring antimicrobial peptides from diverse sources including microorganisms, plants and animals have been isolated and characterized in the past 3 decades, only very few AMPs such as polymyxins and gramicidins are being used clinically; and mainly in topical formulations due to their high systemic toxicities. The major challenges identified with the application of antimicrobial peptides as drugs lie in the high cost in synthesizing long peptide sequences, poor stability and unknown toxicity after systemic administration. In efforts to enhance antimicrobial activities and minimize non-specific toxicities, more researchers are increasingly utilizing naturally occurring antimicrobial peptide or protein sequences as templates to perform chemical modifications such as cyclization, sequence truncations, and substitution with D-, β- or fluorinated-amino acids for the generation of new peptide analogs with broader applications for localized or systemic infections within the body. However, current approaches to optimize naturally occurring antimicrobial peptide sequences remain largely empirical at best, making it extremely difficult to delineate general structure-activity relationships especially against the backdrop of massive sequence and structural diversities. Furthermore, many of the new peptide analogs remain long (20 amino acids or more), which might induce significant immunogenicity and ultimately increase the cost for large scale manufacturing. More importantly, it has been suggested that the use of antimicrobial peptides with sequences that are too close to the host defence antimicrobial peptides may trigger the development of resistance towards innate AMPs that could inevitably compromise natural defences against infections, posing significant health and environmental risks.
At the same time, the rapid emergence of antibiotics resistant bacteria and fungi in both the nosocomial and community settings has created a significant strain on healthcare systems around the world. While global incidences of antibiotics resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) and multidrug-resistant Klebsiella pneumoniae and Acinetobacter spp. have reached epidemic levels, the number of new antibiotics entering the clinical development pipeline has been dismal; with only three new structural classes of antibiotics including the oxazolidinones (linezolid), lipopeptides (daptomycin) and pleuromutilins (retapamulin) entering the market since 2000. This development is especially alarming given that pathogenic bacteria such as S. aureus, Enterobacter and Klebsiella are developing resistance to vancomycin and carbapenems, which are potent antibiotics traditionally reserved as the last line of defence for vulnerable patients in hospitals. With the on-going dearth in small molecular antibiotics development, the design and identification of alternative classes of antimicrobial agents with new modes of action that can effectively overcome drug resistance mechanisms is more pressing than ever.
As the majority of the antimicrobial peptides exert their antimicrobial activities through a rapid and direct membrane lytic mechanism, they possess an inherent advantage in overcoming conventional mechanisms of antibiotics resistance such as the increased expression of drug efflux pumps on microbial membranes, production of drug degradation enzymes or alteration to drug interaction sites acquired by microbes against small molecular antibiotics targeting specific biosynthetic pathways. Significant barriers limiting the successful clinical translation of antimicrobial peptides, however, include high systemic toxicities as a result of poor microbial membrane selectivities, relatively high manufacturing cost (for long peptide sequences) and susceptibility to degradation by proteases present in biological fluids such as blood serum, wound exudates or lacrimal fluids.
In view of the above, there is a need to provide alternative antimicrobial peptides. There is also a need to provide an alternative method of treating microbial infections.